NR4A nuclear receptors support memory enhancement by histone deacetylase inhibitors
Joshua D. Hawk, … , David J. Manglesdorf, Ted Abel
Joshua D. Hawk, … , David J. Manglesdorf, Ted Abel
Published September 10, 2012
Citation Information: J Clin Invest. 2012;122(10):3593-3602. https://doi.org/10.1172/JCI64145.
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Research Article Neuroscience

NR4A nuclear receptors support memory enhancement by histone deacetylase inhibitors

Abstract

The formation of a long-lasting memory requires a transcription-dependent consolidation period that converts a short-term memory into a long-term memory. Nuclear receptors compose a class of transcription factors that regulate diverse biological processes, and several nuclear receptors have been implicated in memory formation. Here, we examined the potential contribution of nuclear receptors to memory consolidation by measuring the expression of all 49 murine nuclear receptors after learning. We identified 13 nuclear receptors with increased expression after learning, including all 3 members of the Nr4a subfamily. These CREB-regulated Nr4a genes encode ligand-independent “orphan” nuclear receptors. We found that blocking NR4A activity in memory-supporting brain regions impaired long-term memory but did not impact short-term memory in mice. Further, expression of Nr4a genes increased following the memory-enhancing effects of histone deacetylase (HDAC) inhibitors. Blocking NR4A signaling interfered with the ability of HDAC inhibitors to enhance memory. These results demonstrate that the Nr4a gene family contributes to memory formation and is a promising target for improving cognitive function.

Authors

Joshua D. Hawk, Angie L. Bookout, Shane G. Poplawski, Morgan Bridi, Allison J. Rao, Michael E. Sulewski, Brian T. Kroener, David J. Manglesdorf, Ted Abel

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Figure 5

NR4A signaling contributes to memory formation and enhancement by HDAC inhibitors.

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NR4A signaling contributes to memory formation and enhancement by HDAC i...
HDAC inhibitors increase Nr4a gene expression, and blocking NR4A signaling prevents memory enhancement by HDAC inhibitors, suggesting a model in which NR4A target genes contribute to memory enhancement by HDAC inhibition. In this figure, arrows represent processes that stimulate gene expression and enhance memory formation. In contrast, blunt ends signify pathways that repress gene expression and limit memory formation. Nucleosomes are indicated by the green barrels that are encircled by the gray ribbon, which illustrates promoter DNA. Acetylation (ac) of the histone proteins that constitute the nucleosome (N) is dictated by a dynamic equilibrium between HDAC and HAT activity. Impairing HAT activity would be predicted to reduce Nr4a gene expression and impair memory formation. As illustrated in this study, blocking HDAC activity increases Nr4a gene expression and enhances memory formation. Also, inhibiting the function of NR4A proteins using a dominant-negative protein blocks memory enhancement by HDAC inhibition and impedes expression of several putative NR4A target genes. The increase in Nr4a gene expression observed after TSA injection after training is accompanied by increased expression of the putative NR4A target genes, Bdnf and Fosl2, two memory-associated genes that may contribute to the molecular mechanism of memory enhancement by HDAC inhibitors.